rs2738466

Variant names:

• chr19-11132089-A-G
• rs2738466
• NM_000527.5:c.*773A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11132089-A-G
• chr19-11132089-A-C
• chr19-11132089-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):​c.*773A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 163,236 control chromosomes in the GnomAD database, including 4,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4164 hom., cov: 31)
  • Exomes 𝑓: 0.20 (274 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.33
• Publications: 25 publications found

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

SPC24 (HGNC:26913): (SPC24 component of NDC80 kinetochore complex) Predicted to be involved in cell division. Located in nucleolus and nucleoplasm. Part of Ndc80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-11132089-A-G is Benign according to our data. Variant chr19-11132089-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.*773A>G		3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.*773A>G		3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.*773A>G		3_prime_UTR	Exon 17 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.*773A>G		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.*773A>G		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000913405.1		c.*773A>G		3_prime_UTR	Exon 18 of 18	ENSP00000583464.1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34671 AN: 152036 Hom.: 4158 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.202 AC: 2237 AN: 11082 Hom.: 274 Cov.: 0 AF XY: 0.194 AC XY: 1113 AN XY: 5734

African (AFR) AF: 0.100 AC: 5 AN: 50

American (AMR) AF: 0.228 AC: 496 AN: 2176

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 12 AN: 88

East Asian (EAS) AF: 0.274 AC: 58 AN: 212

South Asian (SAS) AF: 0.139 AC: 191 AN: 1376

European-Finnish (FIN) AF: 0.206 AC: 122 AN: 592

Middle Eastern (MID) AF: 0.150 AC: 3 AN: 20

European-Non Finnish (NFE) AF: 0.209 AC: 1277 AN: 6120

Other (OTH) AF: 0.163 AC: 73 AN: 448

GnomAD4 genome AF: 0.228 AC: 34693 AN: 152154 Hom.: 4164 Cov.: 31 AF XY: 0.227 AC XY: 16849 AN XY: 74364

African (AFR) AF: 0.175 AC: 7271 AN: 41514

American (AMR) AF: 0.241 AC: 3679 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3466

East Asian (EAS) AF: 0.384 AC: 1980 AN: 5160

South Asian (SAS) AF: 0.193 AC: 931 AN: 4822

European-Finnish (FIN) AF: 0.218 AC: 2303 AN: 10586

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.251 AC: 17085 AN: 68020

Other (OTH) AF: 0.230 AC: 485 AN: 2112

Alfa AF: 0.235 Hom.: 5925

Bravo AF: 0.230

Asia WGS AF: 0.297 AC: 1030 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hypercholesterolemia, familial, 1 (2)
-	-	1	Familial hypercholesterolemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.092
DANN	Benign	0.37
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2738466; hg19: chr19-11242765; COSMIC: COSV52945342; COSMIC: COSV52945342;